3,4-Dihydro-2-alkyl-3-oxo-n-aryl-2H-(1)benzo-thieno(3,2-e)-1,2-thiazine-4-carboxamide-1,1-dioxides

ABSTRACT

##STR1## and pharmaceutically acceptable salts thereof, wherein 
     R 1  is hydrogen, halogen or C 1  to C 4  alkyl; 
     R 2  is hydrogen or C 1  to C 4  alkyl; and Ar is phenyl or phenyl substituted with one or more substituents selected from C 1  to C 4  alkyl, halo, trifluoromethyl, nitro, hydroxyl, halophenyl, or C 1  to C 4  alkoxy. 
     The compounds are useful in treating inflammation or other prostaglandin or leukotriene mediated diseases.

BACKGROUND OF THE INVENTION

The present invention relates to3,4-dihydro-2-alkyl-3-oxo-N-aryl-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxides,methods of preparing such compounds, pharmaceutical compositionscomprising such compounds and the use of such compounds in treatinginflammation (e.g., arthritis) or other prostaglandin or leukotrienemediated diseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2## andpharmaceutically acceptable salts thereof wherein

R¹ is hydrogen, halogen or C₁ to C₄ alkyl;

R² is hydrogen or C₁ to C₄ alkyl; and Ar is phenyl or phenyl substitutedwith one or more substituents selected from C₁ to C₄ alkyl, halo,trifluoromethyl, nitro, hydroxyl, halophenyl, or C₁ to C₄ alkoxy.

The present invention also relates to a pharmaceutical compositionuseful in the treatment of inflammation or other prostaglandin orleukotriene mediated diseases comprising an amount of a compound of theformula I effective to treat inflammation or another prostaglandin orleukotriene mediated disease and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating aprostaglandin or leukotriene mediated disease comprising administeringto a patient in need of such treatment a compound of formula I in anamount effective to treat such disease.

The present invention also relates to intermediates useful in preparingthe foregoing compounds and to methods of preparing the foregoingcompounds.

A preferred embodiment of the invention relates to compounds of theformula I wherein R¹ is hydrogen. Another preferred embodiment relatesto compounds of the formula I wherein R² is methyl. In a more preferredembodiment, R¹ is hydrogen and R² is methyl.

Specific preferred compounds of the present invention include thefollowing:

3,4-Dihydro-2-methyl-1,3-oxo-N-phenyl-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;

N-(4-Fluorophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;

N-(4-Bromophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;

N-(4-trifluoromethylphenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;

N-(2-Methyl-4-nitrophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;and

N-(2,4Difluorophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide.

Other compounds of the present invention are compounds of the formula Iwherein R¹ is H, CH₃, Cl, F, CF₃, NO₂, Br, methoxy, or H; R² is H, CH₃,C₂ H₅,or benzyl; and Ar is substituted phenyl such as2,4-dichlorophenyl, 4-chlorophenyl, methoxyphenyl, nitrophenyl ortrifluoromethylphenyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I may be prepared as shown below in Scheme 1.The compounds of formulae IV, V and VI disclosed in the scheme are novelcompounds. ##STR3##

Thus, chlorosulfonation of 3-methylbenzo[b]thiophene (II) followed byreaction of the intermediate sulfonyl chloride (III) with a C₁ -C₆alkylamine (preferably, methylamine) provides IV. The solvent for bothreactions should be a chlorinated solvent, for example, methylenechloride or dichloroethane. The preferred solvent is methylene chloride.The temperature of the reaction medium for the chlorosulfonationreaction should be about -20° to about 50° C., preferably about 0° C.The temperature of the reaction medium for the second reaction should beabout -10° to about 50° C., preferably about 0° C. The pressure of thereaction medium for the foregoing two reactions is not critical. Forexample, it may be about 0.1 to about 10 atmospheres. The pressure ispreferably ambient pressure, i.e. about one atmosphere.

Lithiation of IV followed by quenching the resultant dianion withgaseous carbon dioxide provides, after acidification, V. An aryllithium(e.g., phenyllithium) or alkyllithium (e.g., methyllithium,ethyllithium, sec-butyllithium, or t-butyllithium) is used to effectlithiation. The preferred reagent is n-butyllithium. The solvent for thelithiation reaction should be an aprotic solvent, for example,tetrahydrofurane, dioxane or dimethoxyethane. The preferred solvent isethyl ether. The temperature of the reaction medium for the lithiationreaction should be about -50° to about 50° C., preferably about -20° toabout 0° C. The pressure is not critical. For example, it may be about0.1 to about 10 atmospheres. The pressure is preferably ambientpressure, i.e. about one atmosphere.

Cyclodehydration of V in the presence of an acid provides VI. Thepreferred acid is p-toluenesulfonic acid. The solvent for thecyclodehydration reaction should be a neutral solvent having a highboiling point, for example, benzene or toluene. The preferred solvent isxylene. The temperature of the reaction medium for the cyclodehydrationreaction should be about 25 to about 250° C., preferably the refluxtemperature of the chosen solvent. The pressure is not critical. Forexample, it may be about 0.1 to about 10 atmospheres. The pressure ispreferably ambient pressure, i.e., about one atmosphere.

Reaction of VI with an aryl isocyanate in a polar solvent (e.g.dimethylsulfoxide) gives a compound of formula I. The aryl isocyanate isa compound of the formula ArNCO wherein Ar is as defined above. Thepreferred solvent is dimethylformamide. The temperature of the reactionmedium for the foregoing reaction should be about -20° to about 100° C.,preferably ambient temperature, i.e. about 20° C. The pressure is notcritical. For example, it may be about 0.1 to about 10 atmospheres. Thepressure is preferably ambient pressure, i.e. about one atmosphere.

Salts of compounds of the formula I may be prepared in a conventionalmanner by reacting a compound of the formula I with an appropriate acidor base, for example, an inorganic base such as an alkali metalhydroxide or an alkaline earth metal hydroxide or an acid such asphosphoric acid or hydrochloric acid.

The activity of the compounds of formula I in the treatment ofpulmonary, asthmatic, allergic and inflammatory diseases may bedetermined by a standard test measuring an agent's ability to inhibitcyclooxygenase and 5-lypoxygenase enzyme activity of rat basophilleukemia (RBL-1) cells. According to this test as described by Jakschicket al., Prostaglandins, 16, 733-747 (1978), and Jakschick et al.,Biochem. Biophys. Res. Commun., 95, 103-110 (1980), a monolayer of RBL-1cells is grown for 1 or 2 days in spinner culture in Eagle's minimumessential medium, 15% heat-inactivated fetal calf serum and anantibiotic/antimycotic mixture. The cells are washed aftercentrifugation and incubated in a buffer. A volume of 0.5 ml of cellsuspension is preincubated at 30° C. for ten minutes with a 1 microliterdimethylsulfoxide (DMSO) solution of the agent to be tested. Theincubation is initiated by simultaneous addition of 5 microliters (¹⁴C)-arachidonic acid in ethanol and 2 microliters calcium ionophore(A-21387) in DMSO for final concentrations of 5 and 7.6 micromolar,respectively. Five minutes later, the incubation is terminated by theaddition of 0.27 ml acetonitrile/acetic acid (100:3). High pressureliquid chromatography is performed using acetonitrile/water/acetic acidsolvent. Radiolabeled prostaglandin D₂ (PGD₂), leukotrine B₄ (LTB₄),5-hydroxyeicosatetraenoic acid (5-HETE), and unreacted arachidonic acidare determined. The inhibitory effect on the cyclooxygenase pathway isassessed from the reduction of PGD₂ levels and the inhibitory effect onthe 5-lipoxygenase pathway is assessed from the decrease in the amountof LTB₄ and 5-HETE.

The compounds of the formula I and their pharmaceutically acceptablesalts are effective inhibitors of mammalian leukotriene or prostaglandinbiosynthesis or both and are thus useful in the treatment of variousleukotriene or prostaglandin mediated conditions. In particular, thecompounds have utility, both as the sole active agent and also incombination with other active agents, for the treatment of variouspulmonary, gastrointestinal, inflammatory, dermatological andcardiovascular conditions such as inflammation, arthritis, allergy,psoriasis, asthma, bronchitis, pulmonary hypertension and hypoxia,peptic ulcers, inflammatory bowel disease or cardiovascular spasm, suchas acute myocardial infarctions, and the like in mammals, especially inhumans. The compounds of the formula I and their pharmaceuticallyacceptable salts are particularly useful in treating arthritis.

For treatment of the various conditions described above, the compoundsof formula I and their pharmaceutically acceptable salts may beadministered to a subject in need of treatment by a variety ofconventional routes of administration, including oral, by injection,topical, rectal, and in an aerosol carrier composition foradministration by inhalation.

The exact dosage of a compound of the present invention will depend uponsuch factors as the age, weight and condition of the patent and theseverity of disease. In general, however, a therapeutically-effectivedose of a compound of formula I or a pharmaceutically acceptable saltthereof will range from 0.01 to 100 mg/kg body weight of the subject tobe treated per day, preferably 0.1 to 50 mg/kg per day.

Although the compounds of formula I and their pharmaceuticallyacceptable salts can be administered alone, they will generally beadministered in admixture with a pharmaceutical carrier selected withregard to the intended route of administration and standardpharmaceutical practice. For example, oral administration may be in theform of tablets containing such excipients as starch or lactose, or inthe form of elixirs or suspensions containing flavoring or coloringagents. In the case of animals, the compounds of the present inventionare advantageously contained in an animal feed or drinking water. Forparenteral injection, they amy be used in the form of a sterile aqueoussolution which may contain other solutes, for example, enough salt orglucose to make the solution isotonic. Other active compounds, includingNSAIDS (non-steroidal antiinflammatory drugs) may be administered alongwith the compounds of the present invention.

The following non-limiting Examples are illustrative of the compounds ofthe present invention. All melting points referred to in the Examplesare uncorrected.

EXAMPLE 1 N-3-Dimethyl-benzo[b]thiophene-2-sulfonamide

To a solution of 3-methylbenzo[b]thiophene (20.0 g, 125.1 mmoles) inchloroform (300 ml, was added dropwise chlorosulfonic acid (22.4 ml),39.6g, 337.9 mmoles) at -5° C. The reaction mixture was stirred at 0° C.for 3 hours, and dry methylamine gas was then bubbled in at 0° C. for 3hours. The reaction mixture was slowly warmed to ambient temperature andthen stirred overnight. The mixture was diluted with ethyl acetate, thenwashed with dilute hydrochloric acid and water, dried (magnesiumsulfate), and concentrated in vacuo to give an oil. This oil waschromatographed on silica gel, eluting with ethyl acetate:methylenechloride (1:39 by volume) to give 5.0 g (15%) of the title compound.Trituration using ether:hexane gave an analytically pure compound, mp124°-127° C.; ms:m/e 241 (m⁺,21), 176(13), 162(24), 146(100); ¹H-nmr(deuteriochloroform):δ7.85 (m,2H), 7.50 (m,2H), 4.64 (m,1H), 2,80(d,3H), 2.72 (s,3H); ir(potassium bromide):3298 cm⁻¹.

Anal. Calcd. for C₁₀ H₁₁ NO₂ S₂ : C, 49.77; H, 4.59; N, 5.80. Found: C,49.66; H, 4.52; N, 5,68.

EXAMPLE 2 2-[(Methylamino)sulfonyl]-benzo[b]thiophene-3-acetic acid

To a solution of N-3-dimethyl-benzo[b]thiophene-2-sulfonamide (1.0 g,4.15 mmoles) in dry tetrahydrofuran (75 ml) was added a 2.0M solution ofn-butyl-lithium in hexane (4.6 ml, 9.13 mmoles) at 0° C. The reactionmixture was stirred at 0° C. for 30 minutes, warmed to 15° C. for 10minutes and then cooled to -20° C. Dry carbon dioxide gas was thenbubbled in for 2 hours. The reaction mixture was poured into water,acidified, and then extracted with ethyl acetate. The organic extractwas washed with water, dried (magnesium sulfate), and then concentratedin vacuo. The resulting solid was triturated using ether:hexane to give633 mg (54%) of analytically pure title compound, mp 190°-192° C.;ms:m/e 285 (m⁺, 7), 241 (8), 176 (13), 162 (24), 146 (100); ¹ H-nmr(deuteriochloroform:dimethylsulfoxide-d.sub. 6): δ7.96 (m,2H), 7.56(m,2H), 6.93 (m,1H), 433 (s,2H), 2.76 (d,3H); ir (potassium bromide):3323, 2942, 1705, cm ⁻¹.

Anal. Calcd. for C₁₁ H₁₁ NO₄ S₂ : C, 46.30; H, 3.89; N, 4.91. Found: C,46.28; H, 3.90; N, 4,82.

EXAMPLE 32-Methyl-2H-[1]benzothieno[3,2-e]-1,2-thiazine-3-(4H)-one-1,1-dioxide

A solution of 2-[(Methylamino)sulfonyl]-benzo-[b]thiophene-3-acetic acid(450 mg, 1.58 mmoles) and p-toluenesulfonic acid (45 mg) in xylenes (100ml) was refluxed in a Dean-Stark trap for 6 hours. The solvent wasevaporated and the resulting solid recrystallized from isopropanol togive the title compound (318 mg) in a yield of 765, mp 175°-178° C.;ms:m/e 267 (m⁺,25), 210(8), 160(5), 146(100); ¹H-nmr(deuteriochloroform): δ7.96 (m,1H), 7,80 (m,1H), 7.58 (m,2H), 4.22(s,2H), 3.38 (5,3H); ir (potassium bromide): 1700 cm⁻¹.

Anal. Calcd. for C₁₁ H₉ NO₃ S₂ : C, 49.42; H, 3.39; N, 5.24. Found: C,49.71; H, 3.40; N, 5.20.

EXAMPLE 4N-Aryl-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxidesA. General Procedure

To a solution of2-methyl-2H-[1]benzothieno[3,2-e]-1,2-thiazine-3-(4H)-one-1,1-dioxide(500 mg, 1.87 mmoles) in dry dimethylformamide (20 ml) was added drytriethylamine (0.29 ml, 210 mg, 2.06 mmoles) at ambient temperature. Thereaction mixture was stirred for 5 minutes and arylisocyanate (2.06mmoles) was then added. The reaction mixture was then stirred for 5hours, poured into ice water and acidified. The resulting precipitatewas filtered, washed with water, and air dried. Recrystallization froman appropriate solvent, indicated below, gave an analytically purecompound.

B.3,4-Dihydro-2-methyl-1,3-oxo-N-phenyl-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide

Using phenyl isocyanate as the aryl isocyanate, the title compound wasobtained in 66% yield as white needles (ethanol:methylene chloride) mp233°-236°; ms:m/e 267(54), 162(10), 146(100) 119(86); ¹H-nmr(dimethylsulfoxide-d₆):δ11.20(s,1H), 8.30-7.12 (m,9H), 5.74)(s,1H), 3.30 (s,3H); ir(potassium bromide):νNH 3294, νCO 1693, 1658cm⁻¹.

Anal. Calcd. for C₁₈ H₁₄ N₂ 0₄ S₂ : C, 55.95; H, 3.65; N, 7.25. Found:C, 55.48; H, 3.55; N, 7.21.

C.N-(4-Fluorophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide

Using 4-fluorophenyl isocyanate as the aryl isocyanate, the titlecompound was obtained in 65% yield as white needles(isopropanol:methylene chloride) mp 250°-253°; ms:m/e 404 (m+,2),267(100), 146(56), 137(38); ¹ H-nmr(dimethylsulfoxide-d₆):δ11.30 (s,1H),8.34-7.22 (m,8H), 5.72 (s,1H), 3.32 (s,3H); ir(potassium bromide):νNH3300, νCO 1696, 1657 cm⁻¹.

Anal. Calcd. for C₁₈ H₁₃ N₂ O₄ S₂ F: C, 53.46; H, 3.24; N, 693. Found:C, 53.31; H, 3.30; N, 6.63.

D.N-(4-Bromophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide

Using 4-bromophenyl isocyanate as the aryl isocyanate, the titlecompound was obtained in 68% yield as white needles(isopropanol:methylene chloride) mp 245°-247°; ms:m/e 267(76), 197(40),171(34) 162(22), 146(100); ¹ H-nmr(dimethylsulfoxide-d₆):δ11.40 (s,1H),8.34-7.64 (m,8H), 5.72 (s,1H), 3.32 (s,3H); ir (potassium bromide):νNH3241, νCO 1697, 1652 cm⁻¹.

Anal. Calcd. for C₁₈ H₁₃ N₂ O₄ S₂ Br: C, 46.46; H 2.82; N, 6.02. Found:C, 45.33; H, 2.81; N, 5.76.

E.N-(4-trifluoromethylphenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide

Using 4-trifluoromethylphenyl isocyanate as the aryl isocyanate, thetitle compound was obtained in 65% yield as white needles(isopropanol:methylene chloride) mp 240°-243°; ms:m/e 267(21), 187(69),168(18) 159(23), 146(100); ¹ H-nmr(dimethylsulfoxide-d₆):δ11.62 (s,1H),8.34-7.54 (m,8H), 5.76 (s,1H), 3.32 (s,3H); ir(potassium bromide):νNH3257, νCO 1698, 1655 cm⁻¹.

Anal. Calcd. for C₁₉ H₁₃ N₂ O₄ S₂ F₃ : C, 50.72; H, 2,88; N, 6.16.Found: C, 49.87; H, 2.87; N, 6.35.

F.N-(2-Methyl-4-nitrophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4carboxamide-1,1-dioxide

Using 2-methyl-4-nitrophenyl isocyanate as the aryl isocyanate, thetitle compound was obtained in 55% yield as white needles (isopropanol)mp 268°-270°; ms:m/e 267 (23), 178(61), 146(100); ¹H-nmr(dimethylsulfoxide-d₆):δ10.78 (s,1H), 8.32-7.72 (m,7H), 6.06(s,1H), 3.02 (s,3H), 2.42 (s,3H); ir(potassium bromide):νNH 3377, νCO1718, 1681 cm⁻¹.

Anal. Calcd. for C₁₉ H₁₅ N₃ O₆ S₂ : C, 51.23; H, 3.39; N, 9.43. Found:C, 50.35; H, 3.30; N, 9.33.

G.N-(2,4-Difluorophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide

Using 2,4-difluorophenyl isocyanate as the aryl isocyanate, the titlecompound was obtained in 66% yield as white needles(isopropanol:methylene chloride) mp 255°-258°; ms:m/e 267(61), 203(14),174(14), 160(13), 155(69), 146(100); ¹H-nmr(dimethylsulfoxide-d₆):δ11.02 (s,1H), 8.32-7.08 (m,7H), 5.98(s,1H), 3.32 (s,3H); ir(potassium bromide):νNH 3365, νCO 1712, 1681cm⁻¹.

Anal. Calcd. for C₁₈ H₁₂ N₂ O₄ S₂ F₂ : C, 51.18; H, 2,86; N, 6.63.Found: C, 51.42; H, 2.93; N, 6.89.

EXAMPLE 5

The title compounds of Examples 4B-4G were assayed according to themethod of Jakschick et al. described above. The compounds were found tohave inhibitory activity against cyclooxygenase or 5-lipoxygenase orboth.

I claim:
 1. A compound of the formula ##STR4## or a pharmaceuticallyacceptable salt thereof whereinR¹ is hydrogen, halogen or C₁ to C₄alkyl; r² is hydrogen or C₁ to C₄ alkyl; and Ar is phenyl or phenylsubstituted with one or more substituents selected from C₁ to C₄ alkyl,halo, trifluoromethyl, nitro, hydroxyl, halophenyl, or C₁ to C₄ alkoxy.2. A compound of the formula I according to claim 1 wherein R¹ ishydrogen.
 3. A compound of the formula I according to claim 1 wherein R²is methyl.
 4. A compound of the formula I according to claim 1 whereinR¹ is hydrogen and R² is methyl.
 5. A compound according to claim 1,said compound being selected from the group consistingof3,4-Dihydro-2-methyl-1,3oxo-N-phenyl-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;N-(4-Fluorophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;N-(4-Bromophenyl)-3,4-dihydro-2-methyl-1,3-oxo2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;N-(4-trifluoromethylphenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;N-(2-Methyl-4-nitrophenyl)-3,4-dihydro-2-methyl--1,3-oxo-2H-[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;andN-(2,4-Difluorophenyl)-3,4-dihydro-2-methyl-1,3-oxo-2H[1]benzothieno[3,2-e]-1,2-thiazine-4-carboxamide-1,1-dioxide;and pharmaceutically acceptable salts of the foregoing compounds.
 6. Apharmaceutical composition for the treatment of inflammation, arthritis,allergy, psoriasis, asthma, bronchitis, pulmonary hypertension,pulmonary hypoxia, peptic ulcers, inflammatory bowel disease orcardiovascular spasm comprising an amount of a compound of claim 1effective in treating one of the foregoing and a pharmaceuticallyacceptable carrier.
 7. A composition according to claim 6, wherein R¹ ishydrogen.
 8. A composition according to claim 6, wherein R² methyl.
 9. Acomposition according to claim 6, wherein R¹ is hydrogen and R² ismethyl.
 10. A method of treating inflammation, arthritis, allergy,bronchitis, pulmonary hypertension, pulmonary hypoxia, peptic ulcers,inflammatory bowel disease, cardiovascular spasm, psoriasis or asthmacomprising administering to a patent in need of such treatment an amountof a compound of claim 1 effective in treating one of the foregoing. 11.A method according to claim 10, wherein R¹ is hydrogen.
 12. A methodaccording to claim 10, wherein R² is methyl.
 13. A method according toclaim 10, wherein R¹ is hydrogen and R² is methyl.
 14. A compound of theformula ##STR5## wherein R¹ is hydrogen, halogen or C₁ to C₄ alkyl andR²is hydrogen or C₁ to C₄ alkyl.